1. Field of the Invention
This invention relates to methods of treating a disease, disorder, or condition, in which increasing the number of regulatory T cells (Treg cells or Tregs) is beneficial, using delta-like ligand 4 (Dll4) antagonists. More specifically, the methods of the invention can prevent, treat or ameliorate diabetes by blocking the binding of Dll4 to a Notch receptor with Dll4 antagonists, thereby increasing the number of Tregs. Furthermore, the invention relates to methods of lowering blood glucose levels, or reducing or blocking the production of auto-antibodies, including those against insulin and glutamic acid decarboxylase 65 (GAD65), respectively, with Dll4 antagonists.
2. Description of Related Art
Interactions between Notch receptors and their ligands represent an evolutionarily conserved pathway important not only for cell fate decisions but also in regulating lineage decisions in hematopoiesis and in the developing thymus (Artavanis-Tsakonas et al. 1999, Science 284:770-776; Skokos et al. 2007; J Exp Med 204:1525-1531; and Amsen et al. 2004, Cell 117:515-526). It has been recently shown that Dll4-Notch1 inhibition leads to a complete block in T cell development accompanied by ectopic appearance of B cells and an expansion of dendritic cells (DC) that can arise from Pro-T cell to DC fate conversion within the thymus (Hozumi et al. 2008, J Exp Med 205(11):2507-2513; Koch et al. 2008, J Exp Med 205(11):2515-2523; and Feyerabend et al. 2009, Immunity 30:1-13). Thus, there is accumulating evidence that Notch signaling is critical for the determination of cell fate decision from hematopoietic progenitor cells. Furthermore, a feedback control of regulatory T cell (Treg) homeostasis by DCs in vivo has been shown (Darrasse-Jéze et al. 2009, J Exp Med 206(9):1853-1862). However, the role of Notch signaling in controlling the origin and the development of DCs and consequently Treg homeostasis is still unknown. This is a question clinically important because identifying new methods of inducing Treg expansion could be used as a treatment for autoimmunity diseases and disorders.
The nucleic acid and amino acid sequences of human Dll4 (hDll4) are shown in SEQ ID NOS:1 and 2, respectively. Dll4 antagonists and their uses are disclosed in WO 2007/143689, WO 2007/070671, WO 2008/076379, WO 2008/042236, and WO/2008/019144.